1. Field of the Invention
The present invention concerns methods of preventing or treating HIV-1 or HIV-2 infection by administering to a human, especially vaginally administering to a female, a tin or silicon protoporphyrin IX or tin mesoporphyrin IX.
2. Background Information
Human immunodeficiency viruses (xe2x80x9cHIVxe2x80x9d) have been known as the causative virus for AIDS (Acquired Immunodeficiency Syndrome). The prevalence of AIDS cases is presently increasing at an alarming rate.
Two related retroviruses that can cause AIDS are human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The genomes of these two viruses are about 50% homologous at the nucleotide level, contain the same complement of genes, and appear to attack and kill the same human cells by the same mechanism.
HIV-1 was identified in 1983. Virtually all AIDS cases in the United States are associated with HIV-1 infection. HIV-2 was isolated in 1986 from West African AIDS patients.
HIV-1 and HIV-2 are retroviruses, in which the genetic material is RNA, rather than DNA. The HIV-1 and HIV-2 viruses carry with them a polymerase (reverse transcriptase) that catalyzes transcription of viral RNA into double-helical DNA.
The viral DNA can exist as an unintegrated form in the infected cell or be integrated into the genome of the host-cell. As presently understood, the HIV enters the T4 lymphocyte where it loses its outer envelope, releasing viral RNA and reverse transcriptase.
The reverse transcriptase catalyzes synthesis of a complementary DNA strand from the viral RNA template. The DNA helix then inserts into the host genome where it is known as the provirus. The integrated DNA may persist as a latent infection characterized by little or no production of virus or helper/inducer cell death for an indefinite period of time. When the viral DNA is transcribed and translated by the infected lymphocyte, new viral RNA and proteins are produced to form new viruses that bud from the cell membrane and infect other cells.
Attempts to treat AIDS with drugs which inhibit reverse transcriptase such as 3xe2x80x2-azido-3xe2x80x2-deoxythymidene (AZT) have not been met with a desirable degree of success. Moreover, there is a potential for toxicity with the use of anti-viral drugs. Thus there is a need for an effective and safe means to prevent and treat AIDS.
HIV infections are transmitted by means such as contaminated intravenous drug needles and through sexual contact. The transmission of HIV by heterosexual sex poses an especially severe problem for women. By the year 2,000, it is estimated that 90% of HIV infection will be acquired via heterosexual intercourse.
The utilization of condoms provides a substantial degree of protection against transmission of HIV infections during sexual intercourse, but a difficulty arises when condoms are not employed. Moreover, the use of condoms appears to be a culturally and socially unacceptable practice in many countries.
Although men can protect themselves from HIV infection by using condoms, women who are sexually active have no similar means. Women can encourage their male sex partners to use a condom, but may not succeed. The female condom, which is just becoming available, is expensive and there is presently no evidence that it prevents transmission of HIV.
Even maintaining a monogamous sexual relationship is no guarantee of safety, for if a woman""s male partner becomes infected, he can pass the virus to her. And as more women are infected, so are more babies.
There is presently frustration in the medical field by the bleak prospect for an effective AIDS vaccine in the near future and the severe limitations of drugs that effectively and safely combat HIV.
There is a need for a safe and effective substance that can be inserted into the vagina to a foam, gel, sponge or other form to kill HIV or prevent it from infecting cells in the body. It is hoped that such substance be used by a woman without her partner""s knowledge.
Several recent reports suggested the potential of porphyrins for chemotherapy of HIV-1 infections (Asanaka, M., Kurimura, T., Toya, H., Ogaki, J. and Kato, Y., (1989), xe2x80x9cAnti-HIV Activity of Protoporphyrinxe2x80x9d, AIDS, 3, 403-404; Levere, R. D. Gong, Y.-F., Kappas, A., Bucher, D. J., Wormser, G. P. and Abraham, N. G. (1991), xe2x80x9cHeme Inhibits Human Immunodeficiency Virus 1 Replication in Cell Cultures and Enhances the Antiviral Effect of Zidovudinexe2x80x9d, Proc. Natl. Acad. Sci. U.S.A., 88, 1756-1759; Dixon, D. W. Schinazi, R. and Marzilli, L. G., (1990), xe2x80x9cPorphyrin As Agents Against the Human Immunodeficiency Virus.xe2x80x9d Ann N.Y. Acad. Sci., 616, 511-513; and Dixon, D. W., Kim, M. S., Kumar, V., Obara, G., Marzilli, L. G. and Schinazi, R. F. (1992), xe2x80x9cAmino- and Hydroxytetraphenylporphyrins with Activity Against the Human Immunodeficiency Virus.xe2x80x9d, Antiviral Chem. Chemother., 3, 279-282).
Porphyrin derivatives competitively inhibiting HIV-1 protease have been designed (DeCamp, D. L., Babxc3xa9, L. M., Salto, R., Lucich, J. L., Koo, M.-S., Kahl, S. B. and Craik, C. S. (1992), xe2x80x9cSpecific Inhibition of HIV-1 Protease by Boronate Porphyrinxe2x80x9d, J. Med. Chem., 35, 3426-3428). The effect of these compounds on HIV-1 replication has not been reported. The predominant binding of some porphyrins to the V3 loop of the HIV-1 envelope glycoprotein gp120, and a correlation between the V3 loop binding capacity of some porphyrins and their antiviral activity have been recently demonstrated (Neurath, A. R., Haberfield, P., Joshi, B., Hewlett, I. K., Strick, N. and Jiang, S. (1991), xe2x80x9cRapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays I. The V3 Loop of gp120 as Target,xe2x80x9d Antiviral Chem. Chemother., 2, 303-312; Neurath, A. R., Strick, N., Haberfield, P. and Jiang, S. (1992), xe2x80x9cRapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. II. Porphyrin Reacting with the V3 Loop of gp120xe2x80x9d, Antiviral Chem. Chemother., 3, 55-63; and Neurath, A. R. (1993), xe2x80x9cB Cell Antigenic Site Mapping of HIV-1 Glycoproteins. In: Immunochemistry of AIDSxe2x80x9d, Chemical Immunology, Vol. 56, E. Norrby ed.), pp. 34-60, Karger, Basel; Neurath, A. R., Strick, N. and Jiang, S. (1993), xe2x80x9cRapid Prescreening for Antiviral Agents Against HIV-1 Based on Their Inhibitory Activity in Site-Directed Immunoassays. Approaches Applicable to Epidemic HIV-1 Strainsxe2x80x9d, Antiviral Chem. Chemother., 4, 207-214; and U.S. Pat. No. 5,230,998, the entire contents of U.S. Pat. No. 5,230,998 being incorporated by reference herein).
Levere , R. D., Gong, Y-F., Kappas, A., Bucher, D. J., Wormser, G. P. and Abraham, N. G., (1991), xe2x80x9cHeme Inhibits Human Immunodeficiency Virus 1 Replication In Cell Cultures and Enhances the Antiviral Effect of Zidovodinexe2x80x9d, PNAS, 88, 1756-1759 concern the study of heme alone and heme together with AZT, on HIV replication in human peripheral blood lymphocytes and in the H9 cell line. The following is noted with respect of Levere et al:
(1) The Levere et al results did not achieve substantial suppression of viral infection using only a metalloporphyrin;
(2) Levere et al report only relatively low activity using heme;
(3) The thrust of Levere et al is to use heme in conjunction with AZT.
WO 89/11277 and U.S. Pat. No. 5,109,016 to Dixon, Schinazi and Marzilli concern a method for inhibiting infection or replication of human immunodeficiency virus comprising administering an effective amount of a porphyrin, porphyrin-like compound or a derivative thereof to inhibit HIV infection in cells.
U.S. Pat. No. 5,109,016 describes the following metals which can be inserted into the tetrapyrrole ring of porphyrin: Fe, Co, Zn, Mo, Ti, Mn, Cr, Ni, Mg, Cu, Tl, In, Ru, V and Au, however, Sn is not described in U.S. Pat. No. 5,109,106.
U.S. Pat. No. 5,109,016 indicates that their results demonstrate that non-metalloporphyrins are generally more active than the metalloporphyrins.
EP 337,598 describes the use of porphyrin and metalloporphyrins to treat diseases caused by HIV.
EP 337,598 describes the following metal coordination compounds of the porphyrin: Mg, Fe (II) (e.g., Heme), Fe (III), FeCl (e.g., Hemin), Co and Cu.
EP 337,598 does not describe tin protoporphyrins.
Levere et al (1991), PNAS, 88, 1756-1759; WO 89/11277; U.S. Pat. No. 5,109,106 and EP 337,598 concern only porphyrin interaction with HIV infected cells, i.e., cells after infection or post-infection. Thus these publications concern only intracellular events, e.g., replication, and are not directed to the prevention of HIV-1 or HIV-2 infection.
Porphyrins having anti-HIV-1 activity in in vitro assays have so far not been tested for antiviral activity in vivo. The correlation between in vitro and in vivo efficacy of spermicide nonoxynol-9 to prevent the genital transmission of simian immunodeficiency virus (SIVxe2x80x9d), a nonhuman primate lentivirus that is closely related to HIV-2, was discussed in C. Miller, N. Alexander, A. Gettie, A. Hendrickx and P. Marx, (1992), xe2x80x9cThe Effect of Contraceptives Containing Nonoxynol-9 On the Genital Transmission of Simian Immunodeficiency Virus in Rhesus Macaquesxe2x80x9d, Fertility and Sterility, 57, 1126-1128. Since Sn-PTP-IX prevents HIV infection in vitro it is considered that these results support the efficacy of local application of Sn-PTP-IX.
The tin complex of protoporphyrin IX (Sn-PTP-IX) is known for use in control of heme metabolism in humans and specifically for suppression of hyperbilirubinemia (Drummond, G. S. and Kappas, A. (1981), xe2x80x9cPrevention of Neonatal Hyperbilirubinemia by Tin Protoporphyryin IX, a Potent Competitive Inhibitor of Heme Oxidation, Proc. Natl. Acad. Sci., U.S.A., 78, 6466-6470; Kappas, A., Drummond, G. S., Simionatto, C. S. and Anderson, K. E. (1984), xe2x80x9cControl of Heme Oxygenase and Plasma Levels of Bilirubin by a Synthetic Heme Analogue, Tin-protoporphyrinxe2x80x9d, Hepatology, 4, 336-341; Kappas, A. and Drummond, G. S. (1986), xe2x80x9cControl of Heme Metabolism With Synthetic Metalloporphyrinsxe2x80x9d. J. Clin. Invest., 77, 335-339; Anderson, K. E., Simionatto, C. S., Drummond, G. S. and Kappas, A. (1986), xe2x80x9cDisposition of Tin-Protoporphyrin and Suppression of Hyperbilirubinemia in Humansxe2x80x9d, Clin. Pharmacol. Ther., 39, 510-520; Kappas, A., Drummond, G. S. Manola, T., Petmezaki, S. and Valaes, T. (1988), xe2x80x9cSn-protoporphyrin Use in the Management of Hyperbilirubinemia in Term Newborns With Direct Coombs-positive ABO Incompatibilityxe2x80x9d, Pediatrics, 81, 485-497; Berglund, L., Angelin, B., Blomstrand, R., Drummond, G and Kappas, A. (1988), xe2x80x9cSn-protoporphyrin Lowers Serum Bilirubin Levels, Decreases Biliary Bilirubin Output, Enhances Biliary Heme Excretion and Potently Inhibits Hepatic Heme Oxygenase Activity in Normal Human Subjectsxe2x80x9d, Hepatology, 8, 625-631; Galbraith, R. A. and Kappas, A. (1989), xe2x80x9cPharmacokinetics of Tin-Mesoporphyrin in Man and the Effects of Tin-Chelated Porphyrin on Hyperexcretion of Heme Pathway Precursors in Patients With Acute Inducible Porphyriaxe2x80x9d, Hepatology, 9, 882-888; Chernick et al (1989), xe2x80x9cSensitivity of Human Tissue Heme Oxygenase to a New Synthetic Metalloporphyrinxe2x80x9d, Hepatology, 10, 365-369 and EP 199,888 to Kappas and Drummond).
Sn-PTP-IX has been heretofore employed for control of psoriasis (Emtestam, L., Berglund, L., Angelin, B., Drummond, G. S. and Kappas, A. (1989), xe2x80x9cTin-protoporphyrin and Long Wave Length Ultraviolet Light in Treatment of Psoriasisxe2x80x9d. Lancet i, 1231-1233 and Emtestam, L., Angelin, B., Berglund, L., Drummond, G. S. and Kappas, A. (1993), xe2x80x9cPhotodynamic Properties of Sn-protoporphyrin: Clinical Investigations and Phototesting in Human Subjectsxe2x80x9d, Acta. Derm. Venereol. (Stockh), 73, 26-30).
The use of Sn-PTP-IX has also been discussed in the following publications: Stevenson, D. K., Rodgers, P. A. and Vreman, H. J. (1989), xe2x80x9cThe Use of Metalloporphyrins for the Chemoprevention of Neonatal Jaundicexe2x80x9d, Am. J. Dis. Child, 143, 353-356; Maines, M. D. and Trakshel, G. M. (1992), xe2x80x9cTin-protoporphyrin: A Potent Inhibitor of Hemoprotein-Dependent Steroidogenesis in Rat Adrenals and Testesxe2x80x9d, J. Pharmacol. Exp. Their., 260, 909-916; and Mark, J. A. and Maines, M. D. (1992), xe2x80x9cTin-protoporphyrin-mediated Disruption In Vitro of Heme Oxygenase-2 Protein Integrity and Activity in Rat Brainxe2x80x9d, Pediatric Research, 32, 324-329).
The combination of Sn-PTP-IX with 1-ascorbic acid may decrease potential phototoxic side effects (Keino, H., Mimura, S., Nagae, H., Banno, T. and Kashiwamata, S. (1993), xe2x80x9cProtection By L-ascorbic Acid Against Phototoxicity in Tin-protoporphyrin-treated Suckling Ratsxe2x80x9d, Biol. Neonate, 63, 183-190).
Sn-PTP-IX was shown to have immunostimulatory Effects in vitro and to enhance the biological activity of xcex3-interferon (Novogrodsky, A., Suthanthiran, M. and Stenzel, K. H. (1989), xe2x80x9cImmune Stimulatory Properties of Metalloporphyrinsxe2x80x9d, J. Immunol., 143, 3981-3987 and Weiss, G., Lutton, J. D., Fuchs, D., Werner-Felmayer, G., Bock, G., Abraham, N. G. Kappas, A., Levere, R. D. and Wachter, H. (1993), xe2x80x9cComparative Effects of Heme and Metalloporphyrins on Interferon-xcex3-mediated Pathways in Monocytic Cells (THP-1)xe2x80x9d, Proc. Soc. Exp. Biol. Med., 202, 470-475).
Tin complexes of porphyrin have not heretofore been tested for anti-HIV-1 activity. Protoporphyrin IX has been shown to be a compound with desirable anti-HIV-1 activity (Neurath et al., (1992), Antiviral Chem. Chemother., 3, 55-63).
In contrast to Sn-PTP-IX, Zn-PTP-IX has approximately 50 times higher ED50 values than Sn-PTP-IX (Trakshel, G. M., Sluss, P. M. and Maines, M. D. (1992), xe2x80x9cComparative Effects of Tin- and Zinc-protoporphyrin on Steroidogenesis: Tin-protoporphyrin is a Potent Inhibitor of Cytochrome P-450-dependent Activities in the Rat Adrenalsxe2x80x9d, Pediatric Research, 31, 196-201).
Heretofore there has been a prejudice in the art against utilizing metal complexes in view of the earlier observation that other metal complexes (Co, Cr, Cu, Fe, Mn, Ni and Zn, respectively) of porphyrin have low, if any, anti-HIV-1 antiviral activity (Neurath et al (1992), Antiviral Chem. Chemother., 3, 55-63). Fe-PTP-IX (hemin) has been shown to have low anti-HIV-1 activity (ED50=23 xcexcg/ml) similar to the activity of other metal derivatives of PTP-IX which have so far been tested. In general, the prior art teaches that metal-porphyrin complexes have significantly lower anti-HIV activity than the corresponding uncomplexed porphyrin.
It is an object of the present invention to provide a method to prevent HIV-1 or HIV-2 infection and more particularly to prevent vaginal and anal transmission of HIV-1 or HIV-2 during sexual intercourse or vaginal transmission during childbirth.
It is another object of the present invention to provide a method to treat humans suffering from HIV-1 or HIV-2 infection.
The aforesaid objects, as well as other objects, aims and advantages are satisfied by the present invention.
The present invention concerns a method of preventing or treating HIV-1 or HIV-2 infection by administering to a human a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of a tin or silicon protoporphyrin IX or a tin or silicon mesoporphyrin IX, or a pharmaceutically acceptable salt thereof, alone or in admixture with a pharmaceutically acceptable diluent (carrier).
The present invention also provides a method of preventing transmission of HIV-1 infection or HIV-2 infection which comprises locally administering to an appropriate region of a human body a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX or a pharmaceutically acceptable salt thereof. Such method is intended to prevent transmission of HIV infection, for example, during close bodily contact between two individuals under conditions which would generally favor HIV transmission, for example, during sexual intercourse or during childbirth.
The phrase xe2x80x9cadministration to an appropriate region of the human bodyxe2x80x9d includes, for example, application of tin protoporphyrin IX or tin mesoporphyrin IX to regions of the human body which come into close contact with another human body, for example, application to the male or female genitalia if the method is intended to prevent transmission during sexual intercourse, and application to the vagina or to a baby""s epidermis if the method is intended to prevent transmission during childbirth.
The term xe2x80x9clocally administratingxe2x80x9d includes any method of administration in which the activity of the tin protoporphyrin IX is substantially confined to the region of the human body to which it is applied, for example, vaginal, rectal or topical administration.
The present invention thus provides a method of preventing vaginal transmission of HIV-1 or HIV-2, either during sexual intercourse or during childbirth (vaginal delivery), by vaginal administration, such as by administering a cream, ointment, lotion, jelly, solution, emulsion or foam formulation containing a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX.
The present invention also therefore relates to a method of preventing transmission of HIV-1 or HIV-2 in a newborn baby by topically administering to the baby soon after childbirth a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of a tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX, either alone or in combination with a carrier.
The present invention is also directed to a contraceptive device (for example, a male or female condom, a contraceptive diaphragm or a contraceptive sponge, for example, a polyurethane foam sponge), for the prevention of pregnancy, the improvement comprises said device having applied thereto an anti-HIV-1 or anti-HIV-2 effective amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition comprising, as active ingredients, (i) a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX or a pharmaceutically acceptable salt thereof and (ii) an effective spermicidal amount of one or more spermicidal agents, for example, nonoxynol-9, benzalkonium chloride, menfegol, gossypol, chlorohexidine and xe2x80x9cBETADINExe2x80x9d (povidone-iodine) alone or in association with at least one pharmaceutical carrier and/or excipient.
The present invention is further directed to a pessary or tampon for vaginal administration, wherein the tampon or pessary comprises, as an active ingredient, a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.
The present invention further relates to a pharmaceutical composition for topical administration comprising a pharmaceutically effective anti-HIV-1 or anti-HIV-2 amount of tin or silicon protoporphyrin IX or tin or silicon mesoporphyrin IX, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable topical carrier or excipient, to form an ointment, cream, gel, lotion, paste, jelly, spray or foam.